Osteoarthritis (OA) is a disease which causes loss of joint function due to damage and deterioration of the articular cartilage. Damage usually begins at the articular surface from long-term wear or trauma, and is characterized by irreversible rupture (fissure) of the collagen fibrillar network within the superficial zone (SZ). SZ damage increases surface porosity, permeability and interstitial fluid exudation, resulting in loss of the cartilage's ability to resist joint compressive loading and increased proteoglycan (PG) loss from the middle and deep zones. Two of the primary mechanisms causing damage to the collagen at the surface are from injurious or excessive mechanical loads (EML) and enzyme cleavage by matrix metalloproteinases (MMPs). Currently there are no therapeutic treatments to repair the surface damage and regain the cartilage's functional properties to prevent progression to OA. The goal of this R21 application is to develop novel non-cell based methods to modify the articulating surface of articular cartilage to regain its ability to resistant damage by EML and MMPs and inhibit progression of matrix degradation. We propose to use new concepts of molecular engineering to modify and repair the articular surface damage, specifically the degraded collagen in the SZ, by repairing (cross-linking) the damaged collagen and replacing (attaching/embedding) the lost macromolecules (SZ proteins) within the SZ to restore extracellular matrix (ECM)function. Our molecularengineering approach is fundamentally different from cartilage engineered scaffolds that rely on cell-based regeneration into tissue having equivalent functional properties. Here we propose to repair damaged cartilage at the molecular level to make it resistant to mechanical and catabolic degradation, and more important, to restore and enhance the tissue's functional properties. Our molecular engineering approach is a "model system" that has the potential for a much broader application for the repair of many types of damaged and diseased musculoskeletal tissues, such as in wound healing of skin, ligaments, tendons, meniscus, and neural tissues. Our overall(long-term) hypothesis is thatonce the functionalproperties of these tissues are reestablished, they will respond metabolically to remodel the extracellular matrix (ECM) to a native state. This proposal represents the first attempt (high risk, high impact) to develop a "non-cellular based, molecular engineering" approach for the repair of damaged tissues to improve their function and survival;that is, improvement in mechanical function and resistance to biologicaldegradation (catabolism). Successfulapplication of this approach will have significant impact on the potential treatment modalities for tissue repair. 1